Bacterial infection of the airway epithelium is often accompanied by mucin overproduction. Some airway diseases are also characterized by mucus hypersecretion. Hypersecretion of mucus can overwhelm the ability of the cilia to function properly, and can result in various pathologies, such as airway mucus plugging and airflow obstruction. Mucus hypersecretion also contributes to chronic infection by shielding bacteria from endogenous and exogenous antibacterial agents. Mucus plugging and bacterial infections create a non-healing injury and can result in chronic influx of inflammatory cells that destroy gas exchange tissue. When severe, these effects result in respiratory function decline, and can be fatal. Diseases that are characteristic for this type of injury include, for example, chronic bronchitis, bronchial pneumonia, cystic fibrosis, chronic asthma, emphysema, usual interstitial pneumonitis and other diseases.
Pseudomonas aeruginosa (PA) is an opportunistic pathogen responsible for pneumonia in immunocompromised patients and chronic lung diseases such as cystic fibrosis. Proinflammatory molecules released by cells after exposure to PA release proinflammatory molecules that recruit leukocytes and enhance the bacteriocidal activity of neutrophils and macrophages. The detailed molecular and cellular events following PA exposure that are responsible for bacterial clearance from the airways are unclear. However, production of proinflammatory mediators by cells exposed to PA can result in severe side effects such as scarring of the lung tissue as a result of antibacterial by-products released by the leukocytes. Flagellin, the major immunogenic protein of the bacterial flagellum, activates MUC1 and other signaling proteins on the surface of cells.
Mucins are a family of high molecular weight glycoproteins secreted from epithelial cells at many body surfaces, including the eyes, pancreatic ducts, gallbladder, prostate, respiratory, gastrointestinal, urinary, and reproductive tracts. Mucins are a major component of mucus, and are responsible for the viscoelastic properties of mucus, and serve a role in protecting and lubricating the epithelial surfaces.
In the airways, mucin proteins form a protective barrier on the airway epithelial cells, and interact with cilia to trap and clear pathogens (e.g., microorganisms), particulate matter, irritants and pollutants (i.e., tobacco smoke and sulfur dioxide). Mucus secretions in the airway are produced from two different secretory cell populations: the surface epithelial goblet cells and the mucous cells in the submucosal glands.
MUC1 is a pattern recognition receptor with binding specificity for bacterial flagellin. It is known that the MUC1 cytoplasmic tail (CT) is highly conserved among species and is phosphorylated on tyrosine and serine residues located within docking sites for SH2 and non-SH2 signaling molecules in response to flagellin binding. Kim, et al., 1996, Expression of MUC1 mucin gene by hamster tracheal surface epithelial cells in primary culture, Am. J. Respir. Cell Mol. Biol. 15: 237-244 4. The cytoplasmic domain of MUC1 contains amino acid sequence motifs that, once phosphorylated, serve as docking sites for a wide variety of signaling adaptor molecules and kinases.
To sense innumerable and various pathogenic threats, Toll-like receptors (TLRs) have evolved to recognize pathogen-associated molecular patterns (PAMPs), which represent molecular features on the surface of pathogens. The various TLRs bind to a variety of PAMPs that work as molecular markers of potential pathogens that the host shall be defended against. For example, TLR's bind lipolysaccharide (LPS) present in bacterial cell walls, DNA-containing unmethylated CpG motifs, double-stranded RNA, and bacteria flagellin.
TLR5 is expressed by both macrophages and epithelial cells in the airways. Interactions between PAMPs and TLRs on resident airway macrophages and epithelial cells, result in the release of proinflammatory cytokines and chemokines, including TNF-α and IL-8 that act to recruit leukocytes to the area where PAMPs are detected by the TLRs. Uncontrolled release of the proinflammatory cytokines and chemokines can be harmful to a patient as the bacteriocidal agents released into the tissue by the leukocytes recruited to the area can result in scarring of the tissue.
Because current therapies are inadequate to effectively treat inflammation especially airway inflammation, there remains a long-felt need in the art for improved methods of treating airway inflammation. The present invention fulfills this need by providing methods of treating airway inflammation.
Other and further objects, features, and advantages will be apparent from the following description of the presently preferred embodiments of the invention, which are given for the purpose of disclosure.